21-substituted thioenol ethers of 20-oxo-pregnanes and 20-oxo-pregnenes



Patented May 27, 1952 ZO-OXO-PREGNAN ES AND NENES XZO-OXO-PREG- Albert Wettstein and Charles Meystre, Basel. Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, J. i

No-Drawing. ApplicationJuly-lO, 1950, Serial No. 173,002. In Switzerland July 25 1949 6 Claims. (01. 260397.5)

The present invention relates to 21-substituted thioenol ethers of 20-oxo-pregnanes and 20-oxo-pregnenes, and to the preparation thereof.

The conversion of ketones into the corresponding enol' ethers is a known reaction in steroid chemistry.' Thus for example 3-, 7-, 12- or 20- oxo-pregnanes, as Well as the corresponding pregnenes, which are unsubstituted in 2l-position, can be converted without noteworthy difficulty into the corresponding enol ethers. However, it has not heretofore been possible to prepare the enol' ethers of the 20-oxo-pregnanes which are'substituted in the ZI-position or of the 2l-substituted 20-oxo-pregnenes. A primary'object of the present inventionis the embodiment of enol ethers-and, more specifically, the thioenol ethersof the'aforesaid 21-substituted 20-oxo-pregnanes and pregnenes, and the development of a method for the preparation thereof.

As set forth in application, Ser. No. 173,001, filed on even date herewith, it has been found that by reacting a 21-substituted 20-oxo-pregnane or pregnene with a mercapto compound, more particularly an alkyl mercaptan, such as methyl mercaptan, ethyl mercaptan, benyl mercaptan and the like, in the presence of an acid catalyst, such for example as hydrochloric acid, sulfuric acid or toluene-sulfonic acid, the thioacetal (mercaptol) of the starting compound is produced. According to the present invention, the-aforesaid object is realized by splitting ofi l mol of mercaptan from the said acyclic thioacetal, thereby converting thesame into the corresponding thioenol ether. The chemistry of the pregnane compounds, in particularthat of the suprarenal, corti al hormones, is thus further enriched.

According to the present process the specified acyclic thioacetals may be treated with mercaptide-forming heavy metal derivatives, such as oxides or inorganic or organic salts, for example chlorides, nitrates, carbonates, acetates, propionates or benzoates of mercury, cadmium, silver, copper, lead, bismuth, cobalt or nickel. The reaction is suitably carried out with exclusion of water and, if desired,in the presence of organic orino'rganic acid-binding agents, such for example as pyridine or collidine or carbonates such as alkali, alkaline earth or heavy metal carbonates. The conversion of the above mentioned acyclic thioacetals into the corresponding thioenol ethers can also be performed by thermal influence. The resultant thioenol ethers of20-j oxo-pregnanes and ZO-oXQ-pregnenes, such as thioenol alkyl ethers and thioenol aralkyl ethers, especialy thioenol methyl-, thioenal ethyl-, thioenol propyl-, thioenol butylor thioenol benzyl ethers are new compounds. Q j

The pregnane-2o-one-thioacetals, or the corresponding pregnene compounds, prepared according to the aforesaid application, Ser. No. 173,001 are substituted in the 21-position by 'a free or functionally converted hydroxyl group, for example an acyloxy group such as acetoxy, propionyloxy, benzoyloxy or tosyloxy group, or an alkoxy group such as a methoxy or ethoxy group, or by a halogen atom-such as chlorine or bromine. They may also bear similar substituents or 0x0 groups in the 6-, 7-, 12- and in particular in the 3- and ll-positions, and they may bear epoxy groups, for example in the 3,9- and 16,17-positions. They can further have double bonds, for example in 3-, 4-, 5-, 11- and/org16- position. Also corresponding-isomeric pregnane derivatives, for example pentacyclic i-pregnane, l7-iso-pregnane or allo-pregnane compounds maybe employed as starting materials.

The new products may be employed as therapeutic agents. valuable'as intermediate products for. the manufacture of .therapeutically active compounds.-. The following examples illustrate the invention the parts being by weight unless otherwise stated and the relationship of parts by weight to parts by volume being the same as that of the kilogram to the liter; the temperatures arejin degrees centigrade.

Example 1 They are however particularly mat mitiga e "v" i tion or,t e mateiiiitaiiwwwiwsemefie pentam 1 or' ljenzene further quantities the above tions are filtered and-the-filtrate brought'-tosdry- 7 new; s e'Phemi-ly -1=esidueis :dissolved' inhexane fche 1 solution -filtered with .-a smalkquanti ty ef f sodium carbonate solution and water, dried and evaporated; The oily reaction product" is the I A -3,21-diacetoxy pregnane 20 one-diethylthioacetal of the formula C Hs -omooocm "6 parts of the A -3,2l-aiaeetexygswneneqo diethyl-thioacetal obtainable according to the preceding paragraph, are boiledior 8.hou1=s under reflux with 7 parts of meric uiii ci;chloridefandfl parts ofcadmium carbonate infibrparts by volume of dry ethanol'using acalcium chloride moisture 1 a seal. Thereupon the whole is filter'ed m ithsuction, the residue washed with acetoneandwhe j filtrate evaporatedin vacuum; 7 The residue thus 1- 1 obtained is'extracted byf boilingwith ether, the l insoluble saltsufiltered with suction and the ether evaserateain va 'uum. FoYaftr acetyla'tiofifthe' residue "i's'nb'w Tfieat'd if'orifl liouildn the water tibn subsetiii'entlylbrouglit to dryness. foil charmed is iiissolizedtinetheranathe ethersdm- 'tidnwashd'with dilute nyarbai iitrieacia, water;

' dilu'tasediumicafbonateisoliitibnandwater driedy and evaporated. -Theoilyip'roducl-gis dissolved in methanoliandthehotlmethanolic solution tratedlwith carbon ifromithe filteredlsdlutibn there separates tlw'u'i 3,21 -'diacetoxy-cfiregnenefw oneth iq endl ethyl fther o'f theformula d I A I 7 at- 3 95 913 menial-trimmer eetuems: x 3 ample. 1') are heated on.the* -'Wa%er=ba1li V i 7 hours together with-3ipartsr0f mercuric chloride,

5 parts by volume of 'byridifie, and parts by volumeof acetic anhydride; r Tlie solution-iisthen evaporated =in v-acuuim and the *residue shaken outmeyeral times withither; The zethereal'isolw carbon -and: "then allowed to c001; :whereupon etwliethevof tfie iormula CH3 B0111 GHaCOO separates put zin crystallineiicrmr :A f-ter recllystiallizaition from hexaneeior ethyl alcohol, it melts at 90-92". Upon further recrystallization a from pentane, the melting point rises to 150-158. By a chromatographic"purification, additional I the a n'e thioenol'ether can beobta' in'el''lrofiftliefriiitl er liquors.

l Examplea waterbath together with parts of mercuric ci1"lor'itle,. 2llparts' by 'volume of pyridine and 40 partsbyvtiumeor acetic anhydride. Following the addition of water, the solution is evaporated in vacuum, and the resiilue is again dissolved in 5 -pa-rts .-by volume o f pyridine =and rio lpartsby volume of acetone; V l he solution is treated with hydrogen sulfide and the formed insdluble slfie ear solution :then

The cl 3?) i i e' diq mfi ei i ii q i' w e ibe r fls solution. and water, them-dried and evaporated; 'Ilfhe oily residue yie1ds,;,aitercrystallizationirom methanoL, crystals which melt unshazanlyl at 774 94"; are -treated,: in -ijhexane'asolutiom with a: small: amount ofactiveqcarbon and then chromatographed over aluminunroxide. ifl'he residue' o'f th'e hexane and benzeneg-f-ractions are: crystallized from;ethanelv and thenj f-romgpen tane whereupon-l the; melting pomt f--therA -3i,=21 diace ot-the'iiomu la.

:spm' n GHn = game e;

fiarafeter sticbrowncoloration 6 it? m'fim e. eent aak'u ction' inc-admire ti'on wit tetramtrometrrariewrficnis "Wei-cal *for the 'mieene1 other and 'maiiiiest ly etional considerable quantities oi tfi en diethyl rthieacetalz are Heated tor waterribathfwitlrzzsparts I parts of ivolmnewfaceticmxihydridtfiahd'25 by'volu me' iaf glacial iaeetimacidl meireactron rated vacuum, and the r residu'e sflissolved'em ether. .1 The r ethereal solution is mm water;dilutesodium carbonateasoliitibnmnd mm an -straw -A v- 3 21 -diacetoxy-pregnene-20-one- V ;diethyI-tHioacetal--are heated for'4 hours on the evaporated in vacuumand-ethe residue taken up i-n ..emer.. etherealisdlution Qiswashed-with toxy:pregnene-fiiwne-thionolethyl ether with water, and is then dried-and evaporated. The residue is dissolved in hexane and the warm solution treated with active carbon. A quantity of A -3,21-diacetoxy-pregnene-20-one crystallizes out of the cooled clear solution. The mother liquors contain the crude A -3,21-diacetoxy-pregnene-20-one-thioenol ethyl ether, which can be purified as described in Example 3 and also gives the characteristic brown coloration with tetranitromethane mentioned in the said example.

Example 5 2 parts of 3,21-diacetoxy-allo-pregnane-20- one are covered with 5 parts by volume of ethyl mercaptan and 10 parts by volume of chloroform. Thereupon, at 20, while stirring and while maintaining a calcium chloride moisture seal, a slow stream of hydrogen chloride is passed over the liquid. After 18 hours, the solution is concentrated in vacuum. The residue is taken up in ether, the ethereal solution is washed with dilute sodium carbonate solution and water dried and evaporated. The oil which remains behind contains the 3,2l-diacetoxy-allo-pregnane-ZO-onediethyl-thioacetal of the formula CzHss CH: CH;

It may be directly used further, or may be converted into the pure oily thioacetal by chromatographic purification over the aluminum oxide.

2 parts of the pure 3,2l-diacetoxy-allo-pregnane-20-one-diethyl-thioacetal obtained as described in the preceding paragraph are heated for 2 hours on the water-bath with 2 parts of mercuric chloride in 5 parts by volume of pyridine and 10 parts by volume of acetic anhydride. The solution is then cooled, diluted with ether and decanted from the precipitate. It is then evaporated in vacuum after addition of water, the residue taken up in ether, the ethereal solution washed with diulte hydrochloric acid and water, and then dried and evaporated. The residue is then chromatographed over 50 parts of aluminum oxide. The evaporated benzene-pentane fractions are recrystallized from methanol and finally from isopropyl ether, small leaflets which melt at 150-154 being obtained. This 3,2l-diacetoxyallo-pregnane-20-one-thioenol ethyl ether of the formula S CrHs CH: OH:

I -o-omcoc-Ha U @0051) I SCgHs Example 6 parts of 3,2l-dihydroxy-l2-acetoxy-pregnane-ZO-one are dissolved in 5 parts by volume of ethyl mercaptan. While stirri'ngfland main-F taining a calcium chloride moistureseal, hydroe CHzC O O CIHQS CH: CH

can be purified by chromatography over aluminum oxide (preferably after acetylation) or may be further used as the crude product.

5 parts of the pure 3,2l-dihydroxy-l2-acetoxypregnane-20-one-diethyl-thioacetal are heated for 2 hours on the water-bath with 10 parts of mercuric chloride in 20 parts by volume of pyridine and '40 parts by volume of acetic anhydride. The solution is evaporated to dryness in vacuum with addition of water, and the residue is taken up in ether. The ethereal solution is washed with dilute hydrochloric acid and water, and is then dried and evaporated. The crude thioenol ether, obtained as residue, is chromatographed over aluminum oxide. The evaporated pentane and benzene fractions are then recrystallized from pentane and give the characteristic prisms of 3,12,21-triacetoxy-pregnane-20-one-thioenol ethyl ether, melting at -1 60 and corresponding to the formula V p Hie 0 0 CH: CH:

lj-CHIO C O CHI This thioenol ether and also its amorphous mother liquors give, in solution in a small quantity of chloroform, a brown coloration with tetranitromethane. According to the above described procedure it is possible to convert other acylic thioacetals of zo-oxo-pregnanes or 20-oxo-pregnanes, for example, Li -3,21-dia.cetoxy-pregnene- 20-one-dibutyl-thioaceta1 or 3,21-dioxy-12-acetoxy-pregnane-20-one-dimethyl-thioacetal into the corresponding 20-thioenol ethers.

Havingfthus disclosed the invention, what is claimed is:

1. A thioenol lower alkyl ether selected from the group consisting of the thioenol lower alkyl ethers of the 20-oxo-pregnanes and 20-oxo-pregnenes, which are substituted in'the 21-position by a member selected from the group consisting of a free hydroxyl group and a hydroxyl group esterified with a lower alkanoic acid.

2. Thioenol lower alkyl ethers of A -20-oxopregnenes, which are substituted in the 2l-position by a member selected from the group consisting of a free hydroxyl group and a hydroxyl group esterified with a lower alkanoic acid.

3. Thioenol lower alkyl ethers of 20-oxo-preg- S CiHi CHsCOO 

1. A THIOENOL LOWER ALKYL ETHER SELECTED FROM THE GROUP CONSISTING OF THE THIOENOL LOWER ALKYL ETHERS OF THE 20-OXO-PREGNANES AND 20-OXO-PREGNENES, WHICH ARE SUBSTITUTED IN THE 21-POSITION BY A MEMBER SELECTED FROM THE GROUP CONSISTING OF A FREE HYDROXYL GROUP AND A HYDROXYL GROUP ESTERIFIED WITH A LOWER ALKANOIC ACID. 